Treatment options for cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma: a systematic review

Purpose There is no agreed-upon standard option for patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC) unfit for cisplatin-based regimens. Therefore, we performed a systematic review to explore alternative options for this population. Methods We searched PubMed, Cochrane, and Embase databases for observational studies and clinical trials (CTs) assessing treatment options for LA HNSCC cisplatin-ineligible patients. This study was registered in PROSPERO under the number CRD42023483156. Results This systematic review included 24 studies (18 observational studies and 6 CTs), comprising 4450 LA HNSCC cisplatin-ineligible patients. Most patients were treated with cetuximab-radiotherapy [RT] (50.3%), followed by carboplatin-RT (31.7%). In seven studies reporting median overall survival (OS) in patients treated with cetuximab-RT, it ranged from 12.8 to 46 months. The median OS was superior to 40 months in two studies assessing carboplatin-RT, and superior to 15 months in two studies assessing RT alone. For other regimens such as nimotuzumab-RT, docetaxel-RT, and carboplatin-RT plus paclitaxel the median OS was 21, 25.5, and 28 months, respectively. Conclusions Our systematic review supports the use of a variety of therapy combinations for LA HNSCC cisplatin-ineligible patients. We highlight the urgent need for clinical studies assessing treatment approaches in this population. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-024-05887-z.


Table S1: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Checklist for the Manuscript (A), and for the Abstract (B). _________________________ 4 (A)
PRISMA checklist for the manuscript._______________________________________4 (B) PRISMA checklist for the abstract.__________________________________________5

Table S13: Incidence of commonly reported adverse events among patients treated with carboplatin-RT (A); cetuximab-RT (B); docetaxel-RT (C); pembrolizumab-RT (D); nimotuzumab-RT (E); carboplatin-RT plus paclitaxel (F); and carboplatin-RT plus cetuximab (G). ____________________________________________________________ 36
Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.
Page 4 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.
Table S2 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Data collection process
9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Page 4, 5 Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Page 5 10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.
Page 5

Study risk of bias assessment
11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
Page 5 Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.

NA Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

NA
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

NA
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
Page 5 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

NA
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).

NA
13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.NA

Reporting bias assessment
14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

NA Certainty assessment
15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
Pages 5 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.
Table S7 Study characteristics 17 Cite each included study and present its characteristics.Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study.Table S11 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

Results of syntheses 20a
For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
Page 10

Section and Topic
Item # Checklist item Location where item is reported 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

Eligibility criteria
3 Specify the inclusion and exclusion criteria for the review.Yes Information sources 4 Specify the information sources (e.g.databases, registers) used to identify studies and the date when each was last searched.

Yes
Risk of bias 5 Specify the methods used to assess risk of bias in the included studies.

CTX:
weekly cetuximab initially at a dose of 400 mg/m2 of body surface area and then at 250 mg weekly during the whole RT.
RT: high-dose radiotherapy; one 2-Gy fraction per day, 5 days a week, for a total of 70 Gy.

Agarwal 2011
Retrospective cohort CTX-RT patients with LASCCHN planned for curative intent treatment but unsuitable or ineligible for platinum-based concurrent chemo-radiotherapy based on decisionmaking in a multi-disciplinary head-neck cancer joint clinic were considered eligible for inclusion.
patients treated with palliative intent or for locoregionally recurrent or metastatic disease were excluded from the study cohort.
CTX:: weekly cetuximab initially at a dose of 400 mg/m2 of body surface area and then at 250 mg weekly during the whole RT.RT: 3D or conventionally fractionated (2 Gy/fraction, 5 fractions/week).
RT: IMRT to the high-risk clinical target volume was delivered daily to a total dose of 69.96 Gy over 6.5 weeks (33 fractions of 2.12 Gy, 5 days/week).Elective areas with the low-risk clinical target volume received a total dose of 52.8 Gy (33 fractions of 1.6 Gy).

Van Der Linden 2013
Retrospective cohort patients treated with first-line RT and CTX or RT for oropharyngeal, hypopharyngeal or laryngeal SCC between January 1, 2007 and December 31, 2010 in two university medical centers.No further selection criteria were applied.
NA RT: regimens used in daily practice were diverse.Preferred regimen was accelerated RT, 35 9 2 Gy, total dose 70 Gy, 6 fractions per week.

Ueki 2023
Phase II trial CB-RT 20 ≤ age ≤ 90; histologically proven HNSCC; treated with radical chemoradiotherapy, i.e., whole-neck irradiation including bilateral levels II-IV; measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; patients with renal dysfunction (30-60 mL/min of estimated glomerular filtration rate aged less than 75 years old; ≥ 75-year-old patients with 40 mL/min of eGFR or better; ECOG of 0 to 2; adequate organ functions 14 days prior to registration.Patients were required to meet the following laboratory criteria: white blood cells > 3000 /mm3; neutrophils > 1500 /mm3; platelets > 100,000 /mm3; and total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) less than two times the upper normal limit.

NA
CB: administered at AUC 2 weekly for seven cycles during the RT period.It was administered at a reduced dose (AUC = 1-1.5) in cases of grade 2 hematological adverse events, and suspended when grade 3 or higher hematological toxicity occurred or when investigators judged it as inappropriate.
RT: administered with high-energy photons of 4-10 MV x-rays at a total dose of 70 Gy in 35 fractions over 7 weeks.3D conformal radiation therapy or IMRT was chosen at the institutional discretion.

Weiss 2020
Phase II trial Pembro-RT patient were required to have untreated stage III-IV (non-metastatic) HNSCC, and a contraindication to cisplatin as defined by: abnormal renal function (GFR< institutional lower limit of institutional normal (<LLN)); abnormal hearing (patient or audiology defined); pre-existing tinnitus; neuropathy (bilateral paresthesias or loss of deep tendon reflexes in upper and/or lower extremities); diabetes mellitus; oncologist-certification that patient would not be considered eligible for high dose cisplatin when given as standard of care (for example, due to age or another medical problem, reason was required to be documented); patient refusal for high dose cisplatin.Patients were required to have ECOG PS 0-1 and normal organ function.
nasopharyngeal carcinoma was excluded, as well as active autoimmune disease, a requirement for immunomodulating medications, active infection or non-infectious pneumonitis.
Pembro: 200mg IV concurrent with radiation, at time points 0, 3 weeks and 6 weeks and for three adjuvant cycles following.
response rate (ORR) according to the regimen used.__________________35 (B) Disease control rate (DCR) according to the regimen used._____________________35

NA20c
Present results of all investigations of possible causes of heterogeneity among study results.NA 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.NA Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.NA Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.NA DISCUSSION Discussion 23a Provide a general interpretation of the results in the context of other evidence.Page 8 23b Discuss any limitations of the evidence included in the review.Page 10 23c Discuss any limitations of the review processes used.Page 10 23d Discuss implications of the results for practice, policy, and future research.information for the review, including register name and registration number, or state that the review was not registered.Page 424b Indicate where the review protocol can be accessed, or state that a protocol was not prepared.Page 4 24c Describe and explain any amendments to information provided at registration or in the protocol.Page 10 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.explicit statement of the main objective(s) or question(s) the review addresses.

Table S2 : Full search strategy used in each database: (A) PubMed; (B) Embase; and (C) Cochrane.
(B) Embase Search ('hnscc'/exp OR hnscc OR 'head and neck' OR 'head and neck squamous cell carcinoma'/exp OR 'head and neck squamous cell carcinoma' OR 'head and neck cancer'/exp OR 'head and neck cancer' OR 'squamous cell carcinoma of the head and neck'/exp OR 'squamous cell carcinoma of the head and neck') AND ('cisplatin'/exp OR cisplatin OR 'chemotherapy'/exp OR chemotherapy OR chemotherapies OR 'platinum'/exp OR platinum OR 'cddp'/exp OR cddp OR 'cis-diamminedichloroplatinum(ii)'/exp OR 'cis-diamminedichloroplatinum(ii)' OR 'platinum diamminodichloride' OR 'cis-platinum'/exp OR 'cis-platinum' OR 'cis platinum'/exp OR '

Table S3 : Eligibility criteria and treatment schedule details of studies included in this systematic review.
weekly cetuximab initially at a dose of 400 mg/m2 of body surface area and then at 250 mg weekly during the whole RT.
RT: 70Gy of IMRT in 35 fractions Ye 2013 Retrospective cohort CTX-RT patients with stage III and IV HNSCC treated with concomitant therapy between August 1, 2007 and July 31, 2010.This time period corresponds with the first approval of the use of CTX with RT in HNSCC.previous head and neck malignancies, primary treatment with surgery, induction chemotherapy or nasopharyngeal primaries.Electronic charts, including RT treatment plans, were reviewed in 262 RT-CIS and 87 RT-CET cases to collect data on treatment, toxicity, response, and outcomes.CTX: RT: standard (70 Gy in 2 Gy daily fractions over 7 weeks), hypofractionated (60 Gy in 2.4 Gy daily fractions over 5 weeks) or concomitant boost (66-70 Gy in 2 Gy fractions with additional second daily fraction once per week separated by greater than 6 h over 5.5-6 weeks) RT.High dose (60-70 Gy) was delivered to the primary and involved nodes, intermediate dose (50-56 Gy) to the uninvolved neck.Most treatment was with IMRT and some with 3D conformal RT. 'NA' was reserved for studies lacking an explicit description of exclusion criteria.AUC: area under the curve; CB: carboplatin; CET: cetuximab CTX: cetuximab; Cis: cisplatin; DTX: docetaxel; EBRT: external beam radiotherapy; ECOG PS: Eastern Cooperative Oncology Group Perfomance Status; HNSCC: head and neck squamous cell carcinoma; HNC: head and neck cancer; IMRT: intensity modulation radiotherapy; NA: not available; N: Number of patients; Nimo: nimotuzumab; PTX: paclitaxel; Pemb: Pembrolizumab; Pembro: pembrolizumab; RT: radiotherapy; 3D: three-dimensional; VMAT: Volumetric modulated arc therapy.

Table S4 : Definition of outcomes according to the information available in studies included in this systematic review.
NA: study does not assess the specific outcome or the outcome definition was not available.

Table S6 : Detailed information regarding tumor staging based on available information of studies included in this systematic review.
Data is given as numbers unless indicated otherwise; AJCC: American Joint Committee on Cancer; CB: carboplatin; CTX: cetuximab; DTX: docetaxel; ECOG PS: Eastern Cooperative Oncology Group Perfomance Status; Ed: edition; NA: not available or subgroup not assessed by the study; N: Number of patients; Nimo: nimotuzumab; PTX: paclitaxel; Pembro: Pembrolizumab; RT: radiotherapy;

Table S7 : List of excluded studies after a comprehensive review.
IMMUNE: A multicenter, prospective, single arm phase II of the combination of durvalumab with carboplatin and paclitaxel as first-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck not eligible to standard chemotherapy(GORTEC 2018-03)randomized study to compare short course palliative radiotherapy with short course concurrent palliative chemotherapy plus radiotherapy in advanced and unresectable head and neck cancer lack of data for the cisplatin-unfit patients Delaruelle 2014 Modified DCF (mDCF, docetaxel cisplatin 5FU) for patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) unfit to DCF: A retrospective study study does not specify if patients are cisplatinunfit Study of Nivolumab or Nivolumab plus Cisplatin, in Combination with Radiotherapy in Patients with Advanced Cancer of the Head and Neck lack of outcomes of interest; only safety outcomes NCT03349710 Nivolumab or Nivolumab Plus Cisplatin, in Combination With Radiotherapy in Patients With Cisplatin-ineligible or Eligible Locally Advanced Squamous Cell Head and Neck International, Multi-Center, Phase I/II, Dose-escalation Trial Investigating the Safety of Zalutumumab, a Human Monoclonal Epidermal Growth Factor Receptor Antibody in Combination with Radiotherapy, in Patients with Stage III, IVa or IVb Locally Advanced Squamous Cell Carcinoma of the Head and Neck Ineligible for Platinum based Chemotherapy -Zalutumumab in combination with radiotherapy in SCCHN patients ineligible for platinum based chemoth International, Multi-Center, Phase I/II, Dose-escalation Trial Investigating the Safety of Zalutumumab, a Human Monoclonal Epidermal Growth Factor Receptor Antibody in Combination with Radiotherapy, in Patients with Stage III, IVa or IVb Locally Advanced Squamous Cell Carcinoma of the Head and Neck Ineligible for Platinum based Chemotherapy -Zalutumumab in combination with radiotherapy in SCCHN patients ineligible for platinum based chemoth Multicenter Two-Stage Adaptive Phase 3 Study of Intravenous Administration of REOLYSIN (Reovirus Type 3 Dearing) in Combination with Paclitaxel and Carboplatin versus the Chemotherapy Alone in Patients with Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck who have Progressed on or after Prior Platinum-Based Chemotherapy study of pirarubicin in patients with advanced recurrent head and neck squamous cell carcinoma.lack of population of interest Mehanna 2019 Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial lack of population of interest Gillson 2019 Radiotherapy plus cetuximab or cisplatin for human papillomavirus (HPV)-positive oropharyngeal cancer: a randomized, multicenter, non-inferiority clinical trial lack of population of interest A phase II randomized trial of pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN): First results of the GORTEC 2015-01 "PembroRad" trial population overlap; another publication from the same study already assessed Bourhis 2020 Pembrolizumab versus cetuximab, concomitant with radiotherapy (RT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Results of the Results of a randomized phase II study comparing pembrolizumab with methotrexate in elderly, frail or cisplatin-ineligible patients with relapsed or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) (ELDORANDO-AIO-KHT-0115) unfinished study due to low recruitment rate Mohan 2021 High Dose Palliative-Intent Intensity Modulated Radiotherapy For Head and Neck Squamous Cell Carcinoma lack of the population of interest Iglesias Phase II multicenter randomized trial to assess the efficacy and safety of first line nivolumab in combination with paclitaxel in subjects with R/M HNSCC unable for cisplatinbased chemotherapy (NIVOTAX): A TTCC study recurrent HNSCC; lack of population of interest Klinghammer 2020 ELDORANDO-Pembrolizumab compared with methotrexate in elderly, frail or cisplatin-ineligible patients with relapsed or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) (ELDORANDO-AIO-KHT-0115 ) Methotrexate plus or minus cetuximab as first-line treatment in a recurrent or metastatic (R/M) squamous cell carcinoma population of the head and neck (SCCHN), unfit for cisplatin combination treatment, a phase Ib-randomized phase II study Commence

Table S9 : Disease-free survival (DFS) at 1 year (A); and 2 years (B), according to the treatment regimen.
: number of patients who achieved certain response or rate; Total: total number of patients; CTX: cetuximab; RT: radiotherapy; Pembro: pembrolizumab; DTX: docetaxel. N

Table S10 : Locoregional control rate (LRC) at 1 year/15 months (A); 2 years (B), 3 years (C); and 4 years (D), according to the treatment regimen. (A) LRC at one year or 15-months Study N Total Proportion Treatment regimen Data cutoff
N: number of patients who achieved certain response or rate; Total: total number of patients; CTX: cetuximab; RT: radiotherapy; CB: carboplatin; Pembro: pembrolizumab.